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Hepatitis C viral sensing by non-parenchymal liver cells (NPC)

非实质肝细胞 (NPC) 感知丙型肝炎病毒

基本信息

批准号：
8662190
负责人：
HUGO Ramon ROSEN
金额：
$ 19.36万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662190
关键词：
Accounting American Antiviral Agents Biliary Blood CD4 Positive T Lymphocytes Cell Communication Cells Chronic Hepatitis C Cirrhosis Coculture Techniques Complex Conditioned Culture Media Dendritic Cells Double-Stranded RNA Endothelial Cells Epithelial Cells Event Faculty Frequencies Functional RNA Future Galactose Binding Lectin Genes Genetic Polymorphism Genetic Transcription Genome Hepatic Hepatic Stellate Cell Hepatitis C Hepatitis C virus Hepatocyte Human Human Cell Line Human Resources IL2RA gene Immune response Immunotherapy In Vitro Individual Infection Interferons Kupffer Cells Laboratories Lead Ligands Link Liver Liver diseases Lymphocyte Mediating MicroRNAs Molecular Natural Immunity Nature Outcome Pathway interactions Patients Pattern Phosphorylation Play Population Population Heterogeneity Postdoctoral Fellow Prevalence Process Production Proteins Reactive Oxygen Species Recovery Regulatory T-Lymphocyte Replicon Role STAT1 gene Signal Pathway Signal Transduction Single Nucleotide Polymorphism Site Small Interfering RNA Staging System T-Lymphocyte Toll-like receptors Transfection Tretinoin United States Viral Virus Virus Diseases Virus Replication Work adaptive immunity anti-hepatitis C cell type cytokine cytosolic receptor genetic association graduate student helicase hepatitis C virus nucleocapsid protein intrahepatic melanoma novel pathogen public health relevance receptor research study response transcription factor virus core

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, with an overall prevalence of ~2%, and an estimated 200 million chronically infected people worldwide. A substantial body of evidence, including work from our laboratory, supports the concept that early events in the coordination and nature of multi-cellular immune responses are critical in determining whether the virus is cleared or whether persistence is established. However, very little is known about the role of non-parenchymal liver cells (NPCs) in mediating anti-HCV responses. We propose to study how plasmacytoid dendritic cells, Kupffer cells and liver sinusoidal endothelial cells sense HCV infection. We present evidence that NPCs can respond to a viral product of hepatitis C (known as a pathogen-associated molecular pattern or PAMP) by producing high levels of Type III IFNs (interferon lambda 3). These intriguing results corroborate the recent studies demonstrating genetic associations with single nucleotide polymorphisms that encode interferon lambda 3 and spontaneous recovery from HCV. Moreover, we have demonstrated that NPCs express HCV core after inoculation with virus or co-culture with infected hepatocytes. We will determine how NPC-derived proteins can inhibit viral replication. Furthermore, we will explore the specific mechanisms by which HCV core protein induces regulatory CD4+ T cells, thus linking innate and adaptive immune responses. The personnel involved in this application include graduate student, post-doctoral fellow and faculty.

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国最常见的血源性感染，总体患病率约为2%，全球估计有2亿慢性感染者。大量证据，包括我们实验室的工作，支持多细胞免疫反应的协调和性质的早期事件在确定病毒是否被清除或是否建立持久性方面至关重要的概念。然而，很少有人知道的作用，非实质肝细胞（NPC）介导抗HCV反应。我们拟研究浆细胞样树突状细胞、枯否细胞和肝窦内皮细胞如何感知HCV感染。我们提出的证据表明，NPC可以通过产生高水平的III型干扰素（干扰素λ 3）来对丙型肝炎的病毒产物（称为病原体相关分子模式或PAMP）做出反应。这些有趣的结果证实了最近的研究表明编码干扰素λ 3的单核苷酸多态性与HCV自发恢复的遗传相关性。此外，我们已经证明，在接种病毒或与感染的肝细胞共培养后，NPC表达HCV核心。我们将确定NPC衍生蛋白如何抑制病毒复制。此外，我们将探讨HCV核心蛋白诱导调节性CD4+ T细胞的具体机制，从而将先天性和适应性免疫反应联系起来。参与本次申请的人员包括研究生、博士后和教职员工。